The development strategy for an effective tetravalent dengue vaccine has consisted of the clinical evaluation of monovalent vaccine candidates for each of the four serotypes with the goal of selecting suitable candidates for inclusion in a tetravalent formulation. Previously, monovalent vaccine candidates were evaluated in a combined total of over 500 human subjects to determine safety, infectivity, and immunogenicity. These studies identified a collection of 6 suitable vaccine candidates: DEN1del30, DEN2/4del30, DEN3del30/31, DEN3-3D4del30, DEN4del30, and DEN4del30-200,201. The selected vaccine candidates were safe and asymptomatic, elicited a robust antibody response in more than 80% of subjects, and were highly infectious (50% infection dose < 10 PFU). Tetravalent studies: Several Phase I clinical studies in adults were completed to evaluate five different tetravalent admixtures of each vaccine candidate. From this set of data, an initial promising admixture (TV003: DEN1del30, DEN2/4del30, DEN3del30/31, DEN4del30) was selected; however, additional expanded clinical evaluation identified a optimal admixture (TV005) that induces an unprecedented level of neutralizing antibody that is both balanced among the serotypes and sufficient to provide sterile immunity against a second dose administered at six months. Both TV003 and TV005 contain the same set of attenuated viruses, although in TV005, the DENV-2 component is present at a 10-fold higher dose than previously formulated in TV003. Following a single dose of TV005, the frequency of seroconversion in vaccinees to the individual serotypes 1 - 4 reached a remarkable 92%, 97%, 97%, and 97%, respectively, with 90% of vaccinees achieving a tetravalent antibody response. These data suggest that a single dose of vaccine may be sufficiently immunogenic, which points to a significant advantage of the LID vaccine compared to other live attenuated DENV vaccines which require two or three doses to achieve a similar result. The selection of an optimal tetravalent admixture has enabled the further development of the vaccine by several manufacturers located in Brazil, India, and Vietnam. Through on-going technological and scientific support, these licensees are making significant progress in the development of the vaccine and Phase 2 trials are underway in Brazil. Through an Interagency Agreement initiated with the Walter Reed Army Institute of Research, a Phase 2 study has been designed to evaluate the tetravalent vaccine in subjects of decreasing age in Bangkok, Thailand. At LID, clinical evaluation of TV003 and TV005 in a single dose vaccination study followed by challenge with a safety-tested DENV-2 stain is currently underway (NCT02021968 and NCT02021968). Should future studies of this vaccine prove it to be efficacious, the vaccine could be a cost-effective means of controlling dengue in endemic areas and a tremendous public health asset.